Combination of dapagliflozin and statins attenuate renal lipotoxicity in high‐fat high‐fructose diet‐induced insulin resistant rats

Abstract

High‐fat high‐fructose diet (HFF) can induce dyslipidemia and lipid accumulation in the kidney which are related to insulin resistance and metabolic syndrome. Dyslipidemia and lipid accumulation in obesity can lead to lipotoxicity and cellular damage particularly kidney injury by activating oxidative stress, fibrotic and apoptotic pathways. This study investigated whether dapagliflozin alone or combined with atorvastatin could improve metabolic parameters, lipid metabolism and lipid accumulation induced kidney injury in HFF‐induced insulin resistant rats. Male Wistar rats were fed with high‐fat diet with 10% fructose in drinking water for 16 weeks. After that, these rats were received drug treatments for 4 weeks; vehicle (HFF), SGLT2 inhibitor dapagliflozin (HFFD), atorvastatin (HFFA) and SGLT2 inhibitor combined with atorvastatin (HFFDA) groups. HFF rats demonstrated insulin resistance, dyslipidemia, and renal dysfunction associated with impaired renal lipid metabolism and lipid accumulation. Lipid accumulation in the kidney could promote renal dysfunction in HFF rats via the activation of oxidative stress, fibrosis and apoptosis. Dapagliflozin treatment could improve insulin resistance, lipid synthesis and lipotoxicity‐related renal oxidative stress, fibrosis and apoptosis leading to reversal of kidney dysfunction in HFF model. The combined treatment (HFFDA group) could also improve metabolic parameters which was not different from single drug treatment (HFFD or HFFA group). Notably, the reduced lipid accumulation in kidney which were linked to the improvement in lipid oxidation was better in the combined treatment group when compared to a single drug treatment. In summary, dapagliflozin combined with atorvastatin treatment exert the beneficial effects on metabolic parameters, lipid metabolism, and lipid accumulation induced kidney injury via the attenuation of oxidative stress, fibrosis and apoptosis in high‐fat high‐fructose diet‐induced insulin resistant model.Support or Funding InformationThailand Research Fund (RSA6080015 AL); the Royal Golden Jubilee PhD program (PhD/0063/2560 LT and AL); the Faculty of Medicine Research Fund, Chiang Mai University (AL and AP); the Graduate Research Scholarship Chiang Mai University (LT); and the Functional Food Research Center for Well‐being, Chiang Mai University (AL).